CN115484954A - Irak1的有效和选择性不可逆抑制剂 - Google Patents
Irak1的有效和选择性不可逆抑制剂 Download PDFInfo
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- CN115484954A CN115484954A CN202180032794.8A CN202180032794A CN115484954A CN 115484954 A CN115484954 A CN 115484954A CN 202180032794 A CN202180032794 A CN 202180032794A CN 115484954 A CN115484954 A CN 115484954A
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Abstract
本公开涉及作为白介素1(IL‑1)受体相关激酶(IRAK)的不可逆抑制剂的化合物;包含所述化合物的药物组合物;以及治疗或预防激酶介导的病症(包括癌症和其他增殖性疾病)的方法。
Description
相关申请
本申请要求于2020年03月23日提交的美国临时申请号62/993,369的优先权,其全部内容在此全文并入。
背景技术
白介素1(IL-1)受体相关激酶(IRAK)是丝氨酸/苏氨酸激酶,其在启动针对外来病原体的先天免疫应答中起关键作用。总共有四种IRAK激酶:IRAK1和IRAK4,其是催化活性激酶,以及IRAK2和IRAK3,其被认为是无催化活性的,因此被归类为“假激酶”(Flannery,S.等,Biochemical Pharmacology,2010,80(12),1981-1991)。IRAK1是普遍表达的,在血液和免疫组织(例如,骨髓、淋巴结、胸腺和外周血)以及血液恶性肿瘤中观察到最高表达(Cao,Z.D.等,Science 1996,271(5252),1128-1131)。IRAK信号转导有助于最终调节NF-KB和IFN调节因子(IRF)的Toll-白介素受体(TIR)下游的多个信号通路(Rao,N.等,Molecular andCellular Biology 2005,25(15),6521-6532)。在NF-KB的情况下,IRAK1通过与MYD88的相互作用介导TIR的下游信号,MYD在配体与IL-1R或TLR结合后迅速募集到受体。随后通过上游信号或通过自身磷酸化对IRAK1进行磷酸化是关键的翻译后修饰和其激活的标志,这允许IRAK1与TRAF6结合,导致IRAK1同源二聚体从MYD88中释放和下游NF-KB激活(Jain,A.等,Frontiers in Immunology 2014,5)。
IRAK1参与先天免疫应答的信号转导网络,使其成为炎症(Rinqwood,L.等,Cytokine 2008,42(1),1-7)、抗病毒应答(Wong,W.,Science of Signaling 2011,4(183),ec203)以及随后激活适应性免疫应答(Gottpati,S.等,Cellular Signaling 2008,20(2),269-276)的关键调控因子。因此,已经对IRAK1在调控这些过程中的生理和病理功能进行了广泛的研究。特别是,这些研究表明,IRAK1抑制是烧伤后心肌收缩功能障碍(Thomas,J.A.等,American Journal of Physiology-Heart and Circulatory Physiology 2002,283(2),H829-H836)、与过度炎症相关的自身免疫性病况(Deng,C.等,Journal of Immunology2003,170(6),2833-2842;Jacob,C.O.,Proceedings of the National Academy ofSciences of the United States of America 2009,106(15),6256-6261)、心肌功能障碍(Thomas J.A.等,American Journal of Physiology-Heart and CirculatoryPhysiology 2003,285(2),H597-H606)、微生物脓毒性应答(Chandra,R.等,Inflammation2013,36(6),1503-1512)、人骨髓增生异常综合征(MDS)和急性髓性白血病(AML)的潜在治疗。IRAK1在一部分乳腺癌中也过表达和过度磷酸化;特别是三阴性乳腺癌(TNBC)。
发明内容
本文提供了一种式I化合物:
或其药学上可接受的盐,其中变量是本文所定义的。
在一个实施方式中,所述式I化合物是式II化合物:
或其药学上可接受的盐。
在另一个实施方式中,所述式I化合物是式III化合物:
或其药学上可接受的盐。
在又一个实施方式中,所述式I化合物是式IV化合物:
或其药学上可接受的盐。
在另外又一个实施方式中,所述式I化合物是式V化合物:
或其药学上可接受的盐。
在一个实施方式中,所述式I化合物是式VI化合物:
或其药学上可接受的盐。
在另一个实施方式中,所述式I化合物是式VII化合物:
或其药学上可接受的盐。
在另一个方面中,本文提供了药物组合物,其包含本文公开的任何化合物或其药学上可接受的盐,和至少一种药学上可接受的载体。
在又一个方面中,本文提供了一种抑制激酶的方法,其包括向有需要的受试者施用有效量的式I化合物或者包含式I化合物和药学上可接受的载体的药物组合物。
在一个方面中,本文提供了一种治疗增殖性疾病的方法,其包括向有需要的受试者施用有效量的式I化合物或者包含式I化合物和药学上可接受的载体的药物组合物。
本公开还提供了试剂盒,其包含选自式I化合物或其药学上可接受的盐的能够抑制激酶的化合物,以及用于治疗增殖性疾病的说明书。
具体实施方式
IRAK1是一种丝氨酸/苏氨酸激酶,其最初于1994年被鉴定出来。其普遍表达,在血液和免疫组织(例如,骨髓、淋巴结、胸腺和外周血)以及血液恶性肿瘤中观察到最高表达。IRAK信号转导有助于Toll-白介素受体(TIR)下游的多个信号通路,其最终调控NF-KB和IFN调控因子(IRF)。在NF-KΒ的情况下,IRAK1通过与MYD88的相互作用介导TIR的下游信号,MYD88在配体与IL-1R或TLR结合后迅速募集到受体。随后通过上游信号或通过自身磷酸化对IRAK1的磷酸化是关键的翻译后修饰和其激活的标志,这允许IRAK1与TRAF6结合,导致IRAK1同源二聚体从MYD88中释放和下游NF-KB激活。
IRAK1参与先天免疫应答的信号转导网络已将酶定义为炎症、抗病毒应答和随后激活适应性免疫应答的关键调节剂。因此,对IRAK1在调节这些过程中的生理和病理功能进行了广泛的研究。特别是,这些研究表明IRAK1抑制可作为烧伤后心肌收缩功能障碍、与过度炎症相关的自身免疫性疾病、心肌功能障碍、微生物脓毒性应答、人骨髓增生异常综合征(MDS)和急性髓性白血病(AML)的潜在治疗。在巨球蛋白血症细胞中,MYD88L265P体细胞突变非常普遍,并通过激活核因子NF-KB导致恶性生长。两个下游信号转导分支,一个包括BTK和一个包括IRAK1,在表达Myd88L265P的WM细胞系中调控NF-KB活化。
由于BTK或IRAK1的基因敲除导致适度的细胞杀伤;因此应使用IRAK1抑制剂来治疗该疾病;并且IRAK1在从目前接受伊布替尼治疗的WM患者WM细胞系分离的活细胞中被激活,且用IRAK1/4抑制剂和BTK抑制剂治疗的原发性患者样本显示出对NF-KB信号传导的增强抑制和更强大的细胞杀伤。尽管IRAK1已在20多年前鉴定得到,并且其在自身免疫和炎症中的关键功能已得到广泛认可,但尚未报道针对开发IRAK1选择性抑制剂的药物化学方面的工作。
定义
下面列出了用于描述本文公开的化合物和组合物的各种术语的定义。这些定义适用于如整个本说明书和权利要求书中所使用的术语,在特定情况下另有限制除外,这些术语或单独地或作为一个更大的组的一部分使用。
除非另有定义,否则本文使用的所有技术和科学术语通常具有与本领域普通技术人员通常所理解的相同的含义。通常,本文使用的命名法及细胞培养、分子遗传学、有机化学和肽化学中的实验室程序是本领域熟知和常用的那些。
如本文所用,冠词“一个(a/an)”是指一个或不止一个(即,至少一个)该冠词的语法对象。举例来说,“一个要素”指的是一个要素或不止一个要素。此外,术语“包括(including和其他形式如include、includes和included)”的使用不是限制性的。
如本文所用,术语“约”将为本领域普通技术人员所理解并将在一定程度上随使用其的上下文而变化。如本文所用,在提及可测量值如量、持续时间等时,术语“约”意在涵盖在指定值的基础上±20%或±10%的变化,包括±5%、±1%和±0.1%,因为这样的变化对于实现所公开的方法是适宜的。
术语“施用”等是指向受试者提供治疗剂。本领域存在多种施用治疗剂的技术,包括但不限于静脉内、口服、气雾剂、肠胃外、眼、肺和局部施用。
术语“治疗(treat/treated/treating/treatment)”包括减少或减轻至少一种与所治疗的状态、病症或疾病相关或由所治疗的状态、病症或疾病引起的症状。在某些实施方式中,治疗包括使有效量的本文公开的化合物与IRAK接触以针对与癌症有关的病况。
如本文所用,术语“预防(prevent/prevention)”指的是如果没有病症或疾病发生则没有病症或疾病发展,或者如果已经有病症或疾病发展则没有进一步地病症或疾病发展。还考虑了预防与病症或疾病相关的一些或全部症状的能力。
如本文所用,术语“患者”、“个体”或“受试者”是指人或非人哺乳动物。非人哺乳动物包括例如家畜和宠物,如羊、牛、猪、犬、猫和海洋哺乳动物。优选地,所述患者、受试者或个体为人。
如本文所用,术语“有效量”、“药学上有效量”和“治疗有效量”是指无毒但足以提供所需生物学结果的药剂的量。该结果可以是疾病的病征、症状或病因的减少或减轻,或生物系统的任何其他期望的改变。任何个体情况下的适宜治疗量可由本领域普通技术人员使用常规实验确定。
如本文所用,术语“药学上可接受的”是指不会消除化合物的生物活性或性质并且相对无毒的材料如载体或稀释剂,即,所述材料可施用于个体而不会引起不希望的生物学效应或以有害方式与包含其的组合物的任何组分相互作用。
如本文所用,术语“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过将现有的酸或碱部分转化为其盐形式而被修饰。药学上可接受的盐的实例包括但不限于碱性残基如胺的无机酸盐或有机酸盐;酸性残基如羧酸的碱金属盐或有机盐;等等。本公开的药学上可接受的盐包括由例如无毒的无机或有机酸形成的母体化合物的常规无毒盐。本公开的药学上可接受的盐可通过常规化学方法从含有碱性或酸性部分的母体化合物合成。通常,这样的盐可通过使游离酸或碱形式的这些化合物与化学计量量的适宜碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备;通常优选非水介质比如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。表述“药学上可接受的盐”不限于单盐或1∶1盐。例如,“药学上可接受的盐”还包括双盐,如双盐酸盐。合适的盐的列表见于Remington’sPharmaceutical Sciences,第17版,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中,其各通过引用整体并入本文。
如本文所用,术语“组合物”或“药物组合物”是指在本公开内有用的至少一种化合物与药学上可接受的载体的混合物。药物组合物便于将化合物施用于患者或受试者。本领域存在多种施用化合物的技术,包括但不限于静脉内、口服、气雾剂、肠胃外、眼、肺和局部施用。
如本文所用,术语“药学上可接受的载体”指的是药学上可接受的材料、组合物或载体,如液体或固体填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料,所述材料涉及在本公开内有用的化合物在患者体内或向患者的携带或运输中以便所述化合物可实现其预期的功能。通常,这样的构建体从身体的一个器官或部分携带或运输至身体的另一个器官或部分。每种载体必须是在与制剂的其他成分(包括在本公开内有用的化合物)相容的意义上“可接受的”,并且对患者无害。可用作药学上可接受的载体的材料的一些实例包括:糖,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉末状黄芪胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油类,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,如丙二醇;多元醇,如甘油、山梨醇、甘露醇和聚乙二醇;酯类,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;表面活性剂;藻酸;无热原水;等渗盐水;林格氏液;乙醇;磷酸盐缓冲溶液;及药物制剂中采用的其他无毒相容物质。
如本文所用,“药学上可接受的载体”还包括任何和所有包衣、抗细菌和抗真菌剂、及吸收延迟剂等,其与在本公开内有用的化合物的活性相容,并且对患者是生理学上可接受的。也可向组合物中掺入补充活性化合物。“药学上可接受的载体”还可包括本文公开的化合物的药学上可接受的盐。可包含在药物组合物中的其他另外的成分是本领域已知的并见述于例如Remington’s Pharmaceutical Sciences(Genaro,Ed.,Mack Publishing Co.,1985,Easton,PA)中,其通过引用并入本文。
“口服剂型”包括处方或预计用于口服施用的单位剂型。在本文提供的药物组合物的一个实施方式中,本文公开的IRAK抑制剂是以口服剂型施用的。
如本文所用,术语“IRAK”指白介素1(IL-1)受体相关激酶并且可以指野生型受体或包含一个或多个突变的受体。
如本文所用,除非另有说明,否则术语“烷基”本身或作为另一取代基的一部分指的是具有指定的碳原子数的直链或支链烃(即,C1-C6烷基指的是具有一至六个碳原子的烷基)并包括直链和支链。实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、新戊基和己基。C1-C6烷基的其他实例包括乙基、甲基、异丙基、异丁基、正戊基和正己基。
如本文所用,术语“烷基胺”是指基团-N(H)-烷基或-N(烷基)2,其中烷基如上文所定义。
如本文所用,短语“氮保护基团”指通过对氮原子进行化学修饰而引入分子中以在随后的化学反应中获得化学选择性的官能团。氮保护基团的实例包括但不限于苄基氧基(Cbz)、叔丁氧基羰基(Boc)、9-芴基甲氧基羰基(Fmoc)、乙酰基(Ac)、苯甲酰基(Bz)、甲苯磺酰基(Ts)和苄基(Bn)。
术语“亚烷基”单独或与其他术语组合使用,指二价烷基连接基团。亚烷基正常对应于具有两个C-H键的烷烃被亚烷基与化合物其余部分的连接点替代。术语“Cn-m亚烷基”指具有n到m个碳原子的亚烷基。亚烷基的实例包括但不限于乙烷-1,2-二基、乙烷-1,1-二基、丙基-1,3-二基、丙基-1,2-二基、丙基-1,1-二基、丁基-1,4-二基、丁基-1,3-二基、丁基-1,2-二基、2-甲基-丙基-1,3-二基等。
如本文所用,术语“烷氧基”是指基团-O-烷基,其中烷基为如本文所定义。举例来说,烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基等。
如本文所用,术语“烯基”是指衍生自烃部分的一价基团,所述烃部分在某些实施方式中含有二至六个或二至八个碳原子并具有至少一个碳-碳双键。烯基基团可以是或可以不是与另一个基团的连接点。术语“烯基”包括但不限于乙烯基、1-丙烯基、1-丁烯基、庚烯基、辛烯基等。
如本文所用,术语“炔基”是指衍生自烃部分的一价基团,所述烃部分在某些实施方式中含有二至六个或二至八个碳原子并具有至少一个碳-碳三键。炔基基团可以是或可以不是与另一个基团的连接点。术语“炔基”包括但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
如本文所用,除非另有说明,否则术语“卤素(halo/halogen)”单独地或作为另一取代基的一部分指的是氟、氯、溴或碘原子,优选氟、氯或溴,更优选氟或氯。
如本文所用,术语“环烷基”指的是具有1、2或3个环的完全饱和的非芳族碳环系统,其中这样的环可以是稠合的。术语“稠合”指的是通过使两个相邻的原子与第一个环共用(即,共享)而存在(即,连接或形成)第二个环。环烷基还包括双环结构,其本质上可以是桥连的或螺环的,其中双环内的每个单独的环具有3-8个原子。术语“环烷基”包括但不限于环丙基、环丁基、环戊基、环己基、双环[3.1.0]己基、螺[3.3]庚基和双环[1.1.1]戊基。
如本文所用,术语“杂环基”或“杂环烷基”指的是含有1、2、3或4个独立地选自N、O和S的杂原子并具有1、2或3个环的非芳族碳环系统,其中这样的环可以是稠合的,其中稠合在上文定义。杂环基还包括双环结构,其本质上可以是桥连的或螺环的,其中双环内的每个单独的环具有3-8个原子并含有0、1或2个N、O或S原子。术语“杂环基”包括环状酯(即,内酯)和环状酰胺(即,内酰胺),还具体包括但不限于环氧基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基(即,烷基)、吡喃基、二烷基、氮杂环丙基、氮杂环丁烷基、吡咯烷基、2,5-二氢-1H-吡咯基、唑烷基、噻唑烷基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、1,3-嗪基、1,3-噻嗪基、2-氮杂双环-[2.1.1]己基、5-氮杂双环[2.1.1]己基、6-氮杂双环[3.1.1]庚基、2-氮杂双环[2.2.1]-庚基、3-氮杂双环[3.1.1]庚基、2-氮杂双环[3.1.1]庚基、3-氮杂双环[3.1.0]-己基、2-氮杂双环-[3.1.0]己基、3-氮杂双环[3.2.1]辛基、8-氮杂双环[3.2.1]辛基、3-氧杂-7-氮杂双环[3.3.1]-壬基、3-氧杂-9-氮杂双环[3.3.1]壬基、2-氧杂-5-氮杂双环-[2.2.1]庚基、6-氧杂-3-氮杂双环[3.1.1]庚基、2-氮杂螺[3.3]庚基、2-氧杂-6-氮杂螺[3.3]庚基、2-氧杂螺[3.3]-庚基、2-氧杂螺[3.5]壬基、3-氧杂螺[5.3]-壬基、2-氮杂螺[3.3]庚烷和8-氧杂双环[3.2.1]辛基。
如本文所用,术语“芳族”是指具有一个或多个多不饱和环并具有芳族特性的碳环或杂环,即具有(4n+2)个离域π(pi)电子,其中n为整数。
如本文所用,术语“芳基”指的是含有1、2或3个环的芳族碳环系统,其中这样的环可以是稠合的,其中稠合在上文定义。如果环是稠合的,则环中之一必须是完全不饱和的并且稠合的环可以是完全饱和的、部分不饱和的或完全不饱和的。术语“芳基”包括但不限于苯基、萘基、茚满基和1,2,3,4-四氢萘基。在一些实施方式中,芳基基团具有6个碳原子。在一些实施方式中,芳基基团具有六至十个碳原子。在一些实施方式中,芳基基团具有六至十六个碳原子。
如本文所用,术语“杂芳基”指的是含有1、2、3或4个独立地选自N、O和S的杂原子并具有1、2或3个环的芳族碳环系统,其中这样的环可以是稠合的,其中稠合在上文定义。术语“杂芳基”包括但不限于呋喃基、噻吩基、唑基、噻唑基、咪唑基、吡唑基、三唑基、四唑基、异唑基、异噻唑基、二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、5,6,7,8-四氢异喹啉基、5,6,7,8-四氢喹啉基、6,7-二氢-5H-环戊并[b]吡啶基、6,7-二氢-5H-环戊并[c]吡啶基、1,4,5,6-四氢环戊并[c]吡唑基、2,4,5,6-四氢环戊并[c]吡唑基、5,6-二氢-4H-吡咯并[1,2-b]吡唑基、6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑基、5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡啶基、4,5,6,7-四氢吡唑并[1,5-a]吡啶基、4,5,6,7-四氢-1H-吲唑基和4,5,6,7-四氢-2H-吲唑基。
应理解,如果芳基、杂芳基、环烷基或杂环基部分可通过不同的环原子(即,示出或描述时未指明具体的连接点)键合或以其他方式连接到指定的部分,则意指所有可能的点,无论是通过碳原子还是例如三价氮原子。例如,术语“吡啶基”指的是2-、3-或4-吡啶基,术语“噻吩基”指的是2-或3-噻吩基,等等。
如本文所用,术语“取代”指一个原子或一组原子已取代氢作为连接到另一个基团的取代基。
如本文所用,术语“任选取代的”指所提及的基团可以被取代或未被取代。在一个实施方式中,所提及的基团任选地被0个取代基取代,即,所提及的基团未被取代。在另一个实施方式中,所提及的基团任选地被一个或多个单独且独立地选自本文所述基团的一个或多个其他基团取代。
化合物
本文提供的化合物是白介素1受体相关激酶(IRKA)的不可逆抑制剂,其可用于治疗激酶介导的病症,包括癌症和其他增殖性疾病。
在一个方面中,本文提供了式I化合物:
或其药学上可接受的盐;
其中
A选自以下:3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基;
B、C和D各自独立地是CH、CR5或N,条件是当m是0时B、C和D不全是CH;
R1是任选地被R8取代1次或2次的5-10元杂芳基;
R3和R4在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、OR9、N(R9)2和SR9,其中烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被1个、2个或3个R9取代;
R5在每次出现时独立地选自以下:卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、OR9、N(R9)2和SR9,其中烷基任选地被1个、2个或3个卤素取代;
R6在每次出现时独立地选自以下:氢、C1-C6烷基和氮保护基团,其中烷基任选地被R9取代;
R7选自以下:氢、C1-C6烷基、OH、CN、NO2、卤素、C1-C6烷氧基和C1-C6烷基胺,其中烷基任选地被1个、2个或3个卤素取代;
R8选自以下:C1-C6烷基、OH、CN、NO2、卤素、C1-C6烷氧基和C1-C6烷基胺,其中烷基任选地被卤素、OH和NH2取代1次、2次或3次;
R9在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基;
替代地,两个R9与其连接的原子一起形成3-8元杂环烷基;
R2选自以下:
L3是键、-NH-或C1-C4亚烷基,任选地其中一个或多个碳独立地被–C(O)–、–O–、–S–、–NRL3a–、–NRL3aC(O)–、–C(O)NRL3a–、–SC(O)–、–C(O)S–、–OC(O)–、–C(O)O–、–NRL3aC(S)–、–C(S)NRL3a–、反式-CRL3b=CRL3b–、顺式–CRL3b=CRL3b–、–C≡C–、–S(O)–、–S(O)O–、–OS(O)–、–S(O)NRL3a–、–NRL3aS(O)–、–S(O)2–、–S(O)2O–、–OS(O)2–、–S(O)2NRL3a–或–NRL3aS(O)2–替代;
RL3a是氢、任选地被R9取代的C1-C6烷基或氮保护基团;
RL3b在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-12元杂环烷基、6-10元芳基和5-8元杂芳基,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地,两个RL3b基团与其连接的原子一起形成3-8元环烷基或4-7元杂环烷基,两者任选地被1个、2个或3个R9取代;
L4是键或任选地被1个、2个或3个R9取代的C1-C6烷基;
每个RE1、RE2和RE3独立地选自以下:氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-12元环烷基、3-12元杂环烷基、6-12元芳基、和5-12元杂芳基、CN、CH2OREE、CH2N(REE)2、CH2SREE、OREE、N(REE)2、SREE,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地,RE1和RE3,或RE2和RE3,或RE1和RE2连接以形成3-8元环烷基或4-7元杂环烷基,两者任选地被1个、2个或3个R9取代;
每个REE独立地选自以下:氢、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地两个REE基团与其连接的原子一起形成4-7元杂环烷基;
RE5是卤素;
RE6是氢、C1-C6烷基或氮保护基团;
每个Y独立地是O、S或NRE7;
RE7是氢、C1-C6烷基或氮保护基团;
m是0或1;
n是0、1、2或3;和
p是0、1、2、3或4。
在一个实施方式中,R2是
在另一个实施方式中,R2是
其中L3是-NH-和Y是O。
在又一个实施方式中,所述式I化合物是式II化合物:
或其药学上可接受的盐。
在另外又一个实施方式中,所述式I化合物是式III化合物:
或其药学上可接受的盐。
在一个实施方式中,所述式I化合物是式IV化合物:
或其药学上可接受的盐。
在另一个实施方式中,所述式I化合物是式Iva化合物:
或其药学上可接受的盐。
在又一个实施方式中,所述式I化合物是式V化合物:
或其药学上可接受的盐。
在另外又一个实施方式中,所述式I化合物是式VI化合物:
或其药学上可接受的盐。
在一个实施方式中,所述式I化合物是式VII化合物:
或其药学上可接受的盐。
在另一个实施方式中,L选自以下
其中R7是任选地被1个、2个或3个卤素取代的C1-C6烷基。
在又一个实施方式中,B是CH、C是CH和D是N。在另外又一个实施方式中,B是CR5、C是CH和D是CH。在一个实施方式中,B是N、C是CH和D是N。在另一个实施方式中,B是CR5、C是CH和D是N。
在又一个实施方式中,n是0。在另外又一个实施方式中,p是0或1。
在一个实施方式中,式I、II或III化合物选自以下:
或其药学上可接受的盐。
在另一个实施方式中,式I、II、IV或Iva化合物选自以下
或其药学上可接受的盐。
在又一个实施方式中,式I、II或V化合物选自以下
或其药学上可接受的盐。
在另外又一个实施方式中,式I、II或VI化合物选自以下:
或其药学上可接受的盐。
在一个实施方式中,式I、II或VII化合物选自以下:
或其药学上可接受的盐。
在另一个方面中,本文提供了式VIII化合物:
或其药学上可接受的盐。
在又一个实施方式中,所述式I化合物是选自以下
或其药学上可接受的盐。
在另一个实施方式中,式I化合物选自以下:表1中的化合物。
表1.
或其药学上可接受的盐。
在一个方面中,本文提供了本文公开的任何式所示的化合物或其药学上可接受的盐,以及药学上可接受的载体。
本文公开的化合物可以互变异构体和光学异构体(例如,对映异构体、非对映异构体、非对映异构体混合物、外消旋混合物等)存在。
本领域通常熟知,将在体内转化以提供式I-VII化合物的任何化合物为本公开的范围内的前药。
在另一个方面中,药物组合物还包含第二活性剂,其中所述第二药剂。在一些实施方式中,所述第二药剂是激酶抑制剂。在其他实施方式中,所述第二药剂是布鲁顿氏酪氨酸激酶(BTK)抑制剂。
在又一个方面中,本公开提供了药物组合物,其包含本文所述的化合物和任选地药学上可接受的赋形剂。
在一个实施方式中,本文所述的药物组合物包含治疗或预防有效量的本文所述的化合物。药物组合物可以用于在有需要的受试者中治疗增殖性疾病,在有需要的受试者中预防增殖性疾病或在受试者、生物样品、组织或细胞中抑制蛋白激酶(例如,IRAK)的活性。在某些实施方式中,增殖性疾病是癌症(例如,淋巴瘤、白血病或骨髓增生异常综合征(MDS))。在某些实施方式中,增殖性疾病是炎性疾病。在某些实施方式中,炎性疾病是类风湿关节炎、克隆氏病或纤维化。在某些实施方式中,增殖性疾病是自身免疫性疾病。
治疗方法
在一个方面中,本文提供了一种在有需要的个体中治疗癌症的方法,其包括向个体施用治疗有效量的式I化合物。在一个实施方式中,癌症选自以下:肺癌、结肠癌、乳腺癌、子宫内膜癌、甲状腺癌、胶质瘤、鳞状细胞癌和前列腺癌。在另一个实施方式中,癌症是非小细胞肺癌(NSCLC)。
在另一个方面中,本文提供了一种在有需要的个体中抑制激酶的方法,其包括向所述个体施用治疗有效量的式I化合物。在一个实施方式中,激酶是IRAK。在另一个实施方式中,激酶是IRAK1。在又一个实施方式中,激酶是IRAK4。
在另一个方面中,本公开提供了用于治疗和/或预防增殖性疾病的方法。可以治疗的示例性增殖性疾病包括与白介素-1受体相关激酶(IRAK)的过表达或活性增加相关的疾病,例如,癌症、良性肿瘤、与血管生成相关的疾病、炎性疾病、自身炎性疾病和自身免疫学疾病。在某些实施方式中,癌症选自以下:胰腺癌、肺癌(例如,小细胞肺癌(SCLC)、非小细胞肺癌)、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、尤文氏肉瘤、骨髓瘤、Waldenstrom氏巨球蛋白血症、骨髓增生异常综合征、骨肉瘤、脑癌、神经母细胞瘤和结直肠癌。
在另一个方面中,本文提供了一种在生物样品或受试者中使用本文所述的化合物抑制激酶(例如,IRAK(例如,IRAK1或IRAK4))活性的方法。在某些实施方式中,所述方法涉及选择性抑制IRAK1。在某些实施方式中,所述方法涉及选择性抑制IRAK4。
本公开还提供了在生物样品或受试者中抑制细胞生长的方法。在又一个实施方式中,本发明提供了一种在生物样品或受试者中诱导细胞凋亡的方法。
本公开提供了用于向有需要的受试者施用有效量的如本文所述的化合物或其药物组合物的方法。还描述了用于使细胞与有效量的如本文所述的化合物或其药物组合物接触的方法。在某些实施方式中,本文所述的方法还包括向受试者施用其他药剂。在某些实施方式中,本文所述的方法还包括使细胞与其他药剂(例如,抗增殖剂)接触。在某些实施方式中,其他药剂是激酶抑制剂(例如,布鲁顿氏酪氨酸激酶(BTK)抑制剂)。本文所述的方法还可以包括在受试者上进行放射疗法、免疫疗法和/或移植。
在又一个方面中,本文提供了一种在有需要的个体中治疗或预防激酶介导的病症的方法,其包括向所述个体施用治疗有效量的式I化合物。
包含IRAK的调控提供了一种治疗、预防或改善疾病的方法,所述疾病包括但不限于癌症和转移、炎症、关节炎、系统性红斑狼疮、皮肤相关疾病、肺部病症、心血管疾病、缺血、神经退行性疾病、肝脏疾病、胃肠道疾病、病毒和细菌感染、中枢神经系统病症、阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、肌萎缩侧索硬化、脊髓损伤和周围神经病变。
在一些实施方式中,本公开的化合物显示出相对于IRAK4对IRAK1更高的抑制。在某些实施方式中,本公开的化合物显示出对IRAK1的抑制是IRAK4的至少2倍、3倍、5倍、10倍、25倍或100倍。在各种实施方式中,本公开的化合物显示出对IRAK1的抑制可达IRAK4的1000倍。在各种实施方式中,本公开的化合物显示出对IRAK1的抑制可达IRAK4的10000倍。
在一些实施方式中,IRAK活性的抑制是通过IC50测量的。
在一些实施方式中,IRAK活性的抑制是通过EC50测量的。
在一些实施方式中,通过本公开的化合物对IRAK的抑制可以通过生物化学测定测量。通过说明性和非限制性实例,可以将均相时间分辨荧光(HTRF)用于使用本问公开的条件和实验参数确定IRAK活性的抑制。例如,HTRF测定可采用浓度为约1μM的底物(例如,生物素-Lck-肽底物);浓度为约0.2nM至约40nM的IRAK;浓度从约0.000282μM到约50μM的抑制剂。例如,在可以显示出IC50值从约1nM至>1μM;从约1nM至约400nM;从约1nM至约150nM;从约1nM至约75nM;从约1nM至约40nM;从约1nM至约25nM;从约1nM至约15nM;或从约1nM至约10nM的这些条件下筛选本公开的化合物。
在一些实施方式中,本公开的化合物不可逆地结合至IRAK。
可以通过EC50值确定抑制剂的效力。如在基本相似的条件下测定的,具有较低EC50值的化合物相对于具有较高EC50值的化合物是更有效的抑制剂。
可以通过IC50值确定抑制剂的效力。如在基本相似的条件下测定的,具有较低IC50值的化合物相对于具有较高IC50值的化合物是更有效的抑制剂。
IRAK1和IRAK4之间的选择性也可以使用细胞增殖测定来测量,其中细胞增殖取决于激酶活性。在一系列抑制剂浓度下(10μΜ、3μΜ、1.1μΜ、330nM、110nM、33nM、11nM、3nM、1nM)进行增殖测定,并计算EC50。
在又一个实施方式中,本公开提供了一种方法IRAK,所述方法包括向有需要的受试者施用有效量的本文公开的化合物或其药学上可接受的盐。在一些实施方式中,所述方法还包括施用第二药剂。在一些实施方式中,第二药剂是抗体。在另一个实施方式中,第二药剂是激酶抑制剂。在又一个实施方式中,第二药剂是布鲁顿氏酪氨酸激酶(BTK)抑制剂。
其他药剂包括但不限于抗增殖剂、抗癌剂、抗血管生成剂、抗盐药、免疫抑制剂、抗菌剂、抗病毒剂、心血管药、降胆固醇药、抗糖尿病药、抗过敏药、避孕药、镇痛剂及其组合。在某些实施方式中,其他药剂是抗增殖剂(例如,抗癌剂)。
在某些实施方式中,其他药剂是伊布替尼。在某些实施方式中,其他治疗剂是蛋白激酶抑制剂(例如,酪氨酸蛋白激酶抑制剂)。在某些实施方式中,其他治疗剂是IRAK(例如,IRAK1或IRAK4)的结合剂或抑制剂。在某些实施方式中,其他治疗剂是IRAK1的结合剂或抑制剂。在某些实施方式中,其他治疗剂是IRAK4的结合剂或抑制剂。在某些实施方式中,其他药剂自以下:表观遗传或转录调节剂(例如,DNA甲基转移酶抑制剂、组蛋白去乙酰化酶抑制剂(HDAC抑制剂)、赖氨酸甲基转移酶抑制剂)、抗有丝分裂药(例如,紫杉烷和长春花生物碱)、激素受体调节剂(例如,雌激素受体调节剂和雄激素受体调节剂)、细胞信号通路抑制剂(例如,酪氨酸蛋白激酶抑制剂)、蛋白稳定性调节剂(例如,蛋白酶体抑制剂)、Hsp90抑制剂、糖皮质激素、全反式维甲酸和其他促进分化剂。在某些实施方式中,本文所述的化合物或药物组合物可以与抗癌疗法联合施用,包括但不限于手术、放射疗法、移植(例如,干细胞移植、骨髓移植)、免疫疗法和化学疗法。
在某些实施方式中,疾病是癌症或增殖性疾病。
在其他实施方式中,疾病是肺癌、结肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃(stomach)癌、皮肤癌、骨癌、胃(gastric)癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈部鳞状细胞癌、白血病、淋巴瘤、骨髓瘤或实体瘤。在其他实施方式中,疾病是肺癌、乳腺癌、胶质瘤、鳞状细胞癌或前列腺癌。在更进一步的实施方式中,疾病是非小细胞肺癌。
在又一个方面中,本文提供了一种治疗激酶介导的病症的方法,其包括向有需要的受试者施用有效量的本文公开的化合物或其药学上可接受的盐。在一些实施方式中,激酶是IRAK。在其他实施方式中,向受试者施用其他治疗剂。在其他实施方式中,化合物和其他治疗剂同时或顺序施用。
在其他实施方式中,疾病是癌症。在其他实施方式中,癌症是肺癌、结肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃(stomach)癌、皮肤癌、骨癌、胃(gastric)癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈部鳞状细胞癌、白血病、淋巴瘤、骨髓瘤或实体瘤。在其他实施方式中,疾病是肺癌、乳腺癌、胶质瘤、鳞状细胞癌或前列腺癌。在更进一步的实施方式中,疾病是非小细胞肺癌。
在本文公开的方法的一个实施方式中,受试者是人。
在另一个方面中,本公开提供了本文所公开的化合物或其药学上可接受的盐用于制备治疗或预防其中IRAK起作用的疾病的药物中的用途。
在一个方面中,本文提供了一种治疗或预防选自以下的病况的方法:自身免疫性疾病、炎性疾病、增殖性和过度增殖性疾病、免疫介导的疾病、骨疾病、代谢疾病、神经和神经退行性疾病、心血管疾病、激素相关疾病、过敏症、哮喘和阿尔茨海默氏病。在其他实施方式中,所述病况选自增殖性病症和神经退行性病症。
在某些实施方式中,待使用本文所述的化合物治疗或预防的增殖性疾病可能与IRAK(例如,IRAK1或IRAK4)的过表达相关。
增殖性疾病可能与IRAK(例如,IRAK1或IRAK4)的异常活性相关。IRAK(例如,IRAK1或IRAK4)的异常活性可能是升高的和/或IRAK的不适当或不希望的活性。细胞周期进程的失调是增殖性疾病的特征,并且大多数增殖性疾病在IRAK一些组分(例如,IRAK1或IRAK4)活性方面存在异常,通常是通过升高和/或不适当的IRAK激活。在某些实施方式中,IRAK不是过表达的,且IRAK的活性是升高的和/或不适当的。在某些实施方式中,IRAK1是过表达的,且IRAK1的活性是升高的和/或不适当的。在某些实施方式中,IRAK4是过表达的,且IRAK4的活性是升高的和/或不适当的。
本公开的一个方面提供了可用于治疗以过度或异常细胞增殖为特征的疾病、病症和病况的化合物。这样的疾病包括但不限于增殖性或过度增殖性疾病和神经退行性疾病。增殖性和过度增殖性疾病的实例包括但不限于癌症。术语“癌症”包括但不限于以下癌症:乳腺癌、卵巢癌、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、胶质母细胞瘤、神经母细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、结直肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡状癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、骨髓病症、淋巴病症、霍奇金氏病、毛细胞癌、口腔和咽(口)癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠癌、直肠癌、大肠癌、直肠癌、脑癌和中枢神经系统癌、慢性骨髓性白血病(CML)和白血病。术语“癌症”包括但不限于以下癌症:骨髓瘤、淋巴瘤或选自胃癌、肾癌、头颈癌、口咽癌、非小细胞肺癌(NSCLC)、子宫内膜癌、肝癌、非霍奇金氏淋巴瘤和肺癌的癌症。
术语“癌症”是指由恶性肿瘤细胞的增殖引起的任何癌症,如肿瘤、赘生物、癌、肉瘤、白血病、淋巴瘤等。例如,癌症包括但不限于间皮瘤、白血病和淋巴瘤如皮肤T-细胞淋巴瘤(CTCL)、非皮肤外周T-细胞淋巴瘤、与人类T-细胞嗜淋巴细胞病毒(HTLV)相关的淋巴瘤如成人T-细胞白血病/淋巴瘤(ATLL)、B-细胞淋巴瘤、急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病、急性髓细胞性白血病、淋巴瘤和多发性骨髓瘤、非霍奇金淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、霍奇金氏淋巴瘤、伯基特淋巴瘤、成人T-细胞白血病淋巴瘤、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)或肝细胞癌。其他实例包括骨髓增生异常综合征、儿童实体瘤如脑肿瘤、神经母细胞瘤、成视网膜细胞瘤、Wilms肿瘤、骨肿瘤和软组织肉瘤、常见的成人实体瘤如头颈癌(例如,口腔癌、喉癌、鼻咽癌和食道癌)、泌尿生殖道癌(例如,前列腺癌、膀胱癌、肾癌、子宫癌、卵巢癌、睾丸癌)、肺癌(例如,小细胞肺癌和非小细胞肺癌)、乳腺癌、胰腺癌、黑色素瘤和其他皮肤癌、胃癌、脑肿瘤、与Gorlin综合征有关的肿瘤(例如,成神经管细胞瘤、脑膜瘤等)和肝癌。可由主题化合物治疗的癌症的另外的示例性形式包括但不限于骨骼肌或平滑肌癌、胃癌、小肠癌、直肠癌、唾液腺癌、子宫内膜癌、肾上腺癌、肛门癌、直肠癌、甲状旁腺癌和垂体癌。
本文描述的化合物可用于预防、治疗和研究的另外的癌症有例如结肠癌、家族性腺瘤性息肉病性癌和遗传性非息肉病性结直肠癌或黑色素瘤。此外,癌症包括但不限于唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺癌(甲状腺髓样癌和甲状腺乳头状癌)、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、睾丸癌、尿道癌、黑色素瘤、脑肿瘤如胶质母细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周原始神经外胚层肿瘤、胆囊癌、支气管癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因氏肉瘤和浆细胞瘤。在本公开的一个方面,本公开提供了一种或多种本公开的化合物在制造用于治疗癌症的医药中的用途,所述癌症包括但不限于本文公开的各种类型的癌症。
在一些实施方式中,本公开的化合物可用于治疗癌症,如结直肠癌、甲状腺癌、乳腺癌和肺癌;和骨髓增殖性病症,如真性红细胞增多症、血小板增多症,伴骨髓纤维化的髓样化生、慢性髓性白血病、慢性粒单核细胞白血病、嗜酸细胞增多综合征、幼年型粒单核细胞白血病和系统性肥大细胞病。在一些实施方式中,本公开的化合物可用于治疗造血功能障碍,特别是急性髓性白血病(AML)、慢性髓性白血病(CML)、急性早幼粒细胞白血病和急性淋巴细胞白血病(ALL)。
如本文所提供的,术语“癌细胞”包括受任何一种上述病况困扰的细胞。
本公开还提供了一种治疗或预防细胞增殖性病症如增生、异型增生和癌前病变的方法。异型增生是病理学家在活检中可识别的癌前病变的最早形式。主题化合物可出于防止所述增生、异型增生或癌前病变继续发展或变成癌性的目的施用。癌前病变的实例可发生在皮肤、食管组织、乳腺和宫颈上皮内组织中。
神经退行性疾病的实例包括但不限于肾上腺脑白质营养不良(ALD)、亚历山大病、阿尔珀氏病、阿尔茨海默氏病、肌萎缩性侧索硬化(Lou Gehrig病)、共济失调性毛细血管扩张症、Batten病(也称为Spielmeyer-Vogt-Sjogren-Batten病)、牛海绵状脑病(BSE)、Canavan病、Cockayne综合征、皮质基底节变性、Creutzfeldt-Jakob病、家族性致命性失眠、额颞叶变性、亨廷顿病、HIV相关痴呆、肯尼迪病、克腊伯氏病、路易体痴呆、神经疏螺旋体病(neuroborreliosis)、Machado-Joseph病(3型脊髓小脑性共济失调)、多系统萎缩症、多发性硬化、发作性睡眠、Niemann Pick病、帕金森氏病、Pelizaeus-Metzbacher病、皮克氏病、原发性侧索硬化症、朊病毒病、进行性核上性麻痹、Refsum氏病、Sandhoff病、Schilder病、恶性贫血继发的脊髓亚急性联合变性、Spielmeyer-Vogt-Sjogren-Batten病(也称为Batten病)、脊髓小脑共济失调(具有不同特征的多种类型)、脊髓性肌萎缩症、Steele-Richardson-Olszewski病、脊髓痨和中毒性脑病。
本公开的另一个方面提供了一种治疗选自增殖性或过度增殖性疾病或神经退行性疾病的疾病或减轻其严重性的方法,所述方法包括向有此需要的受试者施用有效量的化合物或包含化合物的药学上可接受的组合物。
本公开的化合物和组合物作为IRAK抑制剂的活性可体外、体内或在细胞系中测定。体外测定包括确定对激酶活性或活化激酶的ATPase活性的抑制的测定法。备选的体外测定法量化抑制剂与蛋白激酶结合的能力并可或通过在结合之前放射性标记抑制剂、分离抑制剂/激酶复合物和测定结合的放射性标记的量或通过进行其中新的抑制剂与和已知的放射性配体结合的激酶一起孵育的竞争实验来测量。用于测定本公开中用作各种激酶的抑制剂的化合物的详细条件将在下文实施例中阐述。
根据前述内容,本公开还提供了一种在需要这样的治疗的受试者中预防或治疗任何上述疾病或病症的方法,所述方法包括向所述受试者施用治疗有效量的本公开的化合物或其药学上可接受的盐和任选地第二活性剂。对于任何上述用途,所需剂量将随施用方式、待治疗的具体病况和期望的效果而异。
施用/剂量/制剂
用于口服施用的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物外,液体剂型可还含有本领域常用的惰性稀释剂,如例如水或其他溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和失水山梨糖醇的脂肪酸酯及其混合物。除了惰性稀释剂外,口服组合物还可包含辅助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和增香剂。
可注射配制剂(例如,无菌可注射水性或油脂性混悬剂)可根据已知技术使用合适的分散剂或湿润剂和悬浮剂来配制。无菌可注射配制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂、混悬剂或乳剂,例如在1,3-丁二醇中的溶液剂。可采用的可接受的媒介物和溶剂有水、林格氏液、U.S.P.和等渗氯化钠溶液。另外,通常采用无菌的非挥发性油作为溶剂或悬浮介质。为此目的,可采用任何温和的非挥发性油,包括合成的甘油单酯或甘油二酯。另外,在注射剂的制备中使用脂肪酸如油酸。
为了延长药物的作用,常需要减慢药物从皮下或肌内注射的吸收。这可通过使用水溶性较差的结晶或非晶材料的液体悬浮体来实现。然后,药物的吸收速率取决于其溶解速率,溶解速率又可能取决于晶体大小和结晶形式。或者,通过将药物溶解或悬浮在油媒介物中来实现肠胃外施用的药物形式的延迟吸收。
用于直肠或阴道施用的组合物优选为栓剂,其可通过将本公开的化合物与合适的无刺激性赋形剂或载体如可可脂、聚乙二醇或栓剂蜡混合来制备,所述赋形剂或载体在环境温度下为固体但在体温下为液体,因此将在直肠或阴道腔中熔化并释放活性化合物。
类似类型的固体组合物也可用作软和硬填充明胶胶囊中的填充剂,使用赋形剂如乳糖或奶糖和高分子量聚乙二醇等。
所述活性化合物也可呈具有一种或多种如上所述赋形剂的微囊化形式。固体剂型片剂、糖衣丸、胶囊剂、丸剂和颗粒剂可制备为具有包衣和外壳,如肠溶衣、释放控制包衣和药物配制领域中熟知的其他包衣。在这样的固体剂型中,活性化合物可与至少一种惰性稀释剂如蔗糖、乳糖或淀粉混合。除惰性稀释剂外,这样的剂型还可按常规做法包含另外的物质,例如压片润滑剂和其他压片助剂如硬脂酸镁和微晶纤维素。在胶囊剂、片剂和丸剂的情况下,所述剂型还可包含缓冲剂。
用于局部或透皮施用本公开的化合物的剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、散剂、溶液剂、喷雾剂、吸入剂或贴剂。在无菌条件下将活性组分与药学上可接受的载体和可能需要的任何所需防腐剂或缓冲剂混合。眼科制剂、滴耳剂、眼软膏、散剂和溶液剂也涵盖在本公开的范围内。
除了本公开的活性化合物外,软膏剂、糊剂、乳膏剂和凝胶剂还可含有赋形剂如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、有机硅、膨润土、硅酸、滑石和氧化锌或其混合物。
除了本公开的化合物外,散剂和喷雾剂还可含有赋形剂如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂可另外含有惯用喷射剂如氯氟烃。
透皮贴剂具有向身体提供化合物的受控递送的附加优点。这样的剂型可通过将化合物溶解或分配在适当的介质中来制备。也可使用吸收增强剂来增加化合物穿过皮肤的通量。可通过提供速率控制膜或通过将化合物分散在聚合物基质或凝胶中来控制速率。
根据本公开的治疗方法,通过以实现期望的结果所需要的量和时间向受试者如人或其他动物施用治疗有效量的本公开的化合物来在受试者中治疗或预防病症。如本文所用,本公开的化合物的术语“治疗有效量”指的是足以减少受试者中病症的症状的化合物的量。如医学领域中充分理解的,本公开的化合物的治疗有效量将处于适用于任何医学治疗的合理收益/风险比下。
通常,本公开的化合物将以治疗有效量经由本领域已知的任何常见和可接受的方式单独地或与一种或多种治疗剂组合地施用。治疗有效量可随疾病的严重程度、受试者的年龄和相对健康状况、所用化合物的效力及其他因素而差别很大。通常,使用约0.03至2.5mg/kg体重的日剂量据指示会全身性地获得令人满意的结果。在较大的哺乳动物例如人中,指示的日剂量在约0.5mg至约100mg的范围内,方便地以例如每天至多四次的分次剂量或以延迟形式施用。用于口服施用的合适单位剂型包含大约1至50mg活性成分。
在某些实施方式中,本公开的化合物的治疗量或剂量可在约0.1mg/Kg至约500mg/Kg、或者约1至约50mg/Kg的范围内。通常,根据本公开的治疗方案包括每天以单剂量或多剂量向需要这样的治疗的患者施用约10mg至约1000mg的本公开的一种或多种化合物。治疗量或剂量也将随施用途径和与其他药剂共同使用的可能性而异。
在改善受试者的状况后,如果需要,可施用维持剂量的本公开的化合物、组合物或组合。随后,可根据症状将施用的剂量或频率或两者降低至保持改善的状况的水平;当症状已减轻至期望的水平时,应停止治疗。然而,一旦疾病症状复发,受试者可能需要长期的间歇治疗。
然而,应理解,本公开的化合物和组合物的总日用量将由主治医师在合理的医学判断范围内决定。对于任何特定患者的具体抑制剂量将取决于多种因素,包括所治疗的病症和病症的严重程度;采用的具体化合物的活性;采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;采用的具体化合物的施用时间、施用途径和排泄速率;治疗的持续时间;与所采用的具体化合物组合或同时使用的药物;和医学领域中公知的类似因素。
本公开还提供了一种药物组合,例如试剂盒,其包含a)第一药剂,其为呈游离形式或药学上可接受的盐形式的如本文所公开的本公开的化合物,和b)至少一种助剂。试剂盒可包含关于其施用的说明书。
在某些实施方式中,这些组合物任选地还包含一种或多种其他治疗剂。例如,可以将布鲁顿氏酪氨酸激酶(BTK)抑制剂、化学治疗剂或其他抗增殖剂可以与本公开的化合物组合以治疗增殖性疾病和癌症。
可用作药学上可接受的载体的材料的一些实例包括但不限于:离子交换剂;氧化铝;硬脂酸铝;卵磷脂;血清蛋白,如人血清白蛋白;缓冲物质如磷酸盐、甘氨酸、山梨酸或山梨酸钾;饱和植物脂肪酸的偏甘油酯混合物;水;盐或电解质,如硫酸鱼精蛋白;磷酸氢二钠;磷酸氢钾;氯化钠;锌盐;胶态二氧化硅;三硅酸镁;聚乙烯基吡咯烷酮;聚丙烯酸酯;蜡;聚乙烯聚氧乙烯嵌段聚合物;羊毛脂;糖如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉末状黄芪胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油类,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,如丙二醇或聚乙二醇;酯类,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;藻酸;无热原水;等渗盐水;林格氏液;乙醇;和磷酸盐缓冲溶液。此外,根据配制人员的判断,无毒相容的润滑剂如月桂基硫酸钠和硬脂酸镁和着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可存在于组合物中。可将蛋白激酶抑制剂或其药用盐配制成用于向动物或人施用的药物组合物。这些包含有效治疗或预防蛋白激酶介导的病况的量的蛋白抑制剂和药学上可接受的载体的药物组合物是本公开的其他实施方式。
试剂盒
在一个方面中,本文提供了一种试剂盒,其包含能够抑制激酶活性的化合物,所述化合物选自本文公开的一种或多种化合物或其药学上可接受的盐;和关于在治疗癌症中的使用的说明书。
在另一个方面中,本文提供了一种试剂盒,其包含能够抑制IRAK活性的化合物,所述化合物选自本文公开的化合物或其药学上可接受的盐。
在另一个方面中,本公开提供了一种试剂盒,其包含能够抑制激酶活性的化合物,所述化合物选自本文公开的一种或多种化合物或其药学上可接受的盐;第二活性剂;和关于在治疗癌症中的使用说明书。在一些实施方式中,第二活性剂是布鲁顿氏酪氨酸激酶(BTK)抑制剂。在一个实施方式中,BTK抑制剂是伊布替尼。在另一个实施方式中,BTK抑制剂是阿卡替尼。在又一个实施方式中,BTK抑制剂是泽布替尼。
实施例
本公开通过以下实施例和合成路线进一步说明,这些实施例和合成路线不应解释为将本公开的范围或精神限制于本文所述的具体程序。应理解,提供这些实施例是为了说明某些实施方式而不意图由此限制本公开的范围。还应理解,在不背离本公开的精神和/或所附权利要求的范围的情况下,可采取本领域技术人员可想到的各种其他实施方式、修改及其等同物。
缩写
实施例1:化合物006的制备
路线1:
6-溴-N-(5-硝基吡啶-2-基)吡啶酰胺(3)
向6-溴吡啶甲酸(1g,4.95mmol)的DCM(30mL)溶液中加入草酰氯(2.12mL,24.75mmol),然后加入DMF(5滴)。将混合物搅拌1小时,然后除去溶剂。将残留物混悬在吡啶(10mL)中,并且在0℃下滴加5-硝基吡啶-2-胺(688mg,4.85mmol)在吡啶(10mL)中的溶液。添加完成后,将混合物升温至室温并搅拌1小时。使用饱和NaHCO3水溶液淬灭反应,并且用DCM萃取,MgSO4干燥并浓缩。将所得棕色残留物与EtOAc一起研磨以产生棕色沉淀物,将其过滤,N2下干燥并用于下一步骤而无需进一步纯化。m/z ESI预计值:323.11,实测值:324.72
N-(5-氨基吡啶-2-基)-6-溴化吡啶酰胺(4)
向3(1.5g,4.64mmol)的MeOH(30mL)溶液中添加浓HCl(5mL),随后添加SnCl2.2H2O(3.14g,13.93mmol)。将混合物在60℃下搅拌1小时。将混合物冷却至室温,并使用EtOAc稀释。滴加NH4OH以调整pH至6。添加固体Na2CO3以调整pH至10。将混合物过滤并浓缩,得到所需产物,为棕色固体,无需进一步纯化即可使用。m/z ESI预测值:293.12,实测值:294.64
(3R,5S)-5-氨基-1-(叔丁氧羰基)哌啶-3-羧酸(6)
向(3R,5S)-5-(((苄氧基)羰基)氨基)-1-(叔丁氧羰基)-哌啶-3-羧酸(300mg,0.79mmol)的MeOH(30mL)溶液添加10%Pd/C(84mg,0.08mmol)。将用N2吹扫烧瓶,然后连接一个充满H2的气球。将混合物在H2下搅拌2小时,通过硅藻土过滤过滤并浓缩,得到所需化合物,为透明油状物,其无需进一步纯化即可使用(190mg,收率97%)。m/z ESI预测值:244.29,实测值:245.34
(3R,5S)-5-丙烯酰胺-1-(叔丁氧羰基)哌啶-3-羧酸(7)
向(3R,5S)-5-氨基-1-(叔丁氧羰基)哌啶-3-羧酸(190mg,0.77mmol)的THF(10mL)溶液中添加饱和NaHCO3水溶液(10mL),随后添加丙烯酰氯(75μL,0.92mmol),并将混合物搅拌15分钟。用H2O稀释混合物,并使用10%HCl溶液将pH调节至5。使用EtOAc萃取所得溶液,用盐水洗涤,MgSO4干燥并浓缩以获得所需产物,为白色固体,无需进一步纯化即可使用(210mg,收率91%)。m/z ESI预测值:298.34,实测值:298.79
(3S,5R)-3-丙烯酰胺-5-((6-(6-溴吡啶酰胺)吡啶-3-基)氨甲酰基)-哌啶-1-羧酸叔丁酯(8)
向N-(5-氨基吡啶-2-基)-6-溴化吡啶酰胺(200mg,0.68mmol)、HATU(519mg,1.36mmol)和(3R,5S)-5-丙烯酰胺-1-(叔丁氧羰基)哌啶-3-羧酸(203mg,0.68mmol)的DMF(5mL)溶液添加DIEA(592μL,3.4mmol)。将混合物在室温下搅拌30min,然后通过反相HPLC纯化,使用1至80%ACN/H2O的梯度,得到所需化合物,为白色固体(280mg,收率72%)。m/z ESI预测值:573.45,实测值:574.52
N-(5-((3R,5S)-5-丙烯酰胺哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)-吡啶酰胺(006)
将(3S,5R)-3-丙烯酰胺-5-((6-(6-溴吡啶酰胺)吡啶-3-基)氨甲酰基)-哌啶-1-羧酸叔丁酯(250mg,0.44mmol)溶解在1,4-二烷(5mL)中。添加1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二硼烷-2-基)-1H-吡唑(146mg,0.52mmol),随后添加Na2CO32M水溶液(1.1mL,2.19mmol)。将混合物在超声仪中脱气2分钟。添加Pd(dppf)Cl2(38mg,0.05mmol)和t-BuXPhos(33mg,0.08mmol),并将混合物在密封小瓶中加热至90℃,持续1小时。用水(10mL)淬灭反应,并用EtOAC(2x50mL)萃取,使用盐水洗涤、MgSO4干燥并浓缩。将粗物质溶解在DCM(10mL)中,博并添加TFA(1mL)。将混合物搅拌60分钟,并真空除去溶剂。通过反相HPLC纯化粗物质,以获得所述化合物,为白色固体(41mg,收率20%)。m/z预测值:460.50,实测值:461.19;1H NMR(500MHz DMSO)δ11.04(Br,1H),10.45(s,1H),9.07(m,1H),8.90(m,1H),8.69(d,J=3Hz,1H),8.35(d,J=8Hz,1H),8.28(d,J=8Hz,1H),8.15-8.06(m,3H)7.75(Br,1H),7.06(d,J=2Hz,1H),6.25-6.11(m,2H),5.67(dd,J=3Hz,10Hz,1H),4.15(m,1H),2.98,(m,3H),2.74(m,2H),2.27(m,1H),1.63(m,1H)。
实施例2:化合物002的制备
路线2:
((1R,3S)-3-((6-(6-溴吡啶酰胺)吡啶-3-基)氨甲酰基)环己烷)-氨基甲酸叔丁酯(12)
将N-(5-氨基吡啶-2-基)-6-溴化吡啶酰胺(200mg,0.68mmol)溶解在DMF(2mL)中。添加(1S,3R)-3-((叔丁氧羰基)氨基)环己烷-1-羧酸(183mg,0.75mmol),然后添加HATU(519mg,1.36mmol)和DIEA(0.59mL,3.4mmol)。将混合物在室温下搅拌直至原料消耗。使用水(10mL)淬灭反应,并用EtOAc萃取(2x50mL),用盐水洗涤、MgSO4干燥和浓缩。将所得固体用乙酸乙酯研磨,过滤并干燥,得到产物,无需进一步纯化即可使用。m/z预测值:518.42,实测值:520.04。
N-(5-((1S,3R)-3-丙烯酰胺环己烷-1-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(13)
((1R,3S)-3-((6-(6-溴吡啶酰胺)吡啶-3-基)-氨甲酰基)环己基)氨基甲酸叔丁酯(90mg,0.174mmol)在DCM(3mL)的混悬液中添加TFA(0.3mL)。将澄清溶液搅拌60分钟,并真空除去溶剂。将出品溶解在THF(2mL)中,向其中添加饱和NaHCO3(aq)(2mL),随后缓慢滴加丙烯酰氯(21μL,0.258mmol)。将其在室温下搅拌直至通过LC/MS监测初始原料消耗。通过添加水淬灭反应,并使用EtOAc(2x10mL)萃取,用盐水洗涤、MgSO4干燥和浓缩。粗品无需进一步纯化即可继续使用。m/z预测值:473.48,实测值:474.07。
N-(5-((1S,3R)-3-丙烯酰胺环己烷-1-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)-吡啶酰胺(002)
进行与006同样的操作,得到22mg产物,收率为59.8%。m/z预测值:459.51,实测值:460.20。1H NMR(500MHz DMSO)δ11.26(br,1H),10.14(s,1H),9.02(br,1H),8.70(s,1H),8.23(d,J=8.5Hz,1H),8.12-8.05(m,5H),7.67(br,1H),7.05(s,1H),6.52(br,1H),6.22-6.16(m,1H),6.06(dd,J=13Hz,2Hz,1H),5.56(dd,J=10Hz,2Hz,1H),3.72-3.68(m,1H),3.43,3.12-3.06(m,1H),1.39-1.32(m,3H),1.18-1.15(m,3H)。
实施例3:化合物026的制备
路线3:
((1R,3S)-3-((4-(6-溴吡啶酰胺)苯基)氨甲酰基)环己基)氨基甲酸叔丁酯(17)
将(4-(6-溴吡啶酰胺)苯基)氨基甲酸叔丁酯(200mg,0.51mmol)溶解在DCM(3mL)中,并添加TFA(0.6mL)。将其在室温下搅拌一小时,并真空除去溶剂。向溶解在DMF(2mL)的粗品中添加(1S,3R)-3-((叔丁氧羰基)氨基)环己烷-1-羧酸(183mg,0.75mmol)、DIEA(0.6mL,3.42mmol)、HATU(520mg,1.37mmol),并在室温下搅拌。将反应混合物混悬在乙酸乙酯中,超声处理并过滤。针对是否存在产物,在LC/MS上检查滤液和固体。使用EtOAc(2x10mL)重复洗涤固体,并在真空下干燥过夜,得到48mg白色固体,其无需任何进一步纯化即可继续使用。m/z预测值:517.42,实测值:419.14(无Boc基团的产物)
N-(4-((1S,3R)-3-丙烯酰胺环己烷-1-羧酰氨基)苯基)-6-溴化吡啶酰胺(18)
进行与13同样的操作,得到40mg白色固体其无需进一步纯化即可继续使用。m/z预测值:471.36,实测值:473.11
N-(4-((1S,3R)-3-丙烯酰胺环己烷-1-羧酰氨基)苯基)-6-(1H-吡唑-5-基)-吡啶酰胺(026)
进行与005同样的操作,得到7mg黄色固体。m/z预测值:471.36,实测值:473.11。1HNMR(500MHz,DMSO)δ10.69(br,1H),9.93(s,1H),8.10-8.04(m,4H),7.79(s,2H),7.64(s,2H),7.11(br,1H),6.53(br,1H),6.22-6.16(m,1H),6.06(dd,J=13Hz,2Hz,1H),5.56(dd,J=10Hz,2Hz,1H),3.72-3.70(m,1H),1.96-1.94(m,1H),1.84-1.81(m,4H),1.41-1.34(m,4H)。
实施例4:化合物027-030的制备
路线4:
(S)-3-((6-(6-溴吡啶酰胺)吡啶-3-基)氨甲酰基)哌啶-1-羧酸叔丁酯(22)
向小瓶中添加N-(5-氨基吡啶-2-基)-6-溴化吡啶酰胺(500mg,1.71mmol,(S)-1-(叔丁氧羰基)哌啶-3-羧酸(430.2mg,1.87mmol),HATU(1.3g,3.42mmol)和DMF(3mL)。在室温下向搅拌混合物中滴加DIEA(1.49mL,8.55mmol),并搅拌直至反应完成。用水淬灭反应,用乙酸乙酯稀释。将水层用乙酸乙酯(3x20mL)萃取,合并,用盐水洗涤,MgSO4干燥并浓缩。通过快速层析(含10-50%乙酸乙酯的己烷)纯化粗品,得到550mg产物,收率为64%。m/zESI预计值:504.39,实测值(M+H)+:505.76。1H NMR(500MHz DMSO):δ10.24(s,1H),10.10(s,1H),8.61(s,1H),8.20-8.17(m,2H),8.08(dd,J=8.9Hz,2.6Hz,1H),8.03(t,J=7.8Hz,1H),7.95(d,J=7.85Hz,1H),4.09-3.96(m,1H),3.85(d,J=13.9Hz,1H),2.78(t,J=12.2Hz,1H),2.48-2.43(m,1H),1.97-1.94(m,1H),1.73-1.70(m,1H),1.67-1.58(m,1H),1.42(s,9H),1.38-1.36(m,2H)。
(S)-N-(5-(1-丙烯酰基哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(23)
根据13的程序制备得到52mg产物,其无需进一步纯化即可使用。m/z ESI预测值:458.32,实测值(M+H)+:459.77
(S)-N-(5-(1-丙烯酰基哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(027)
根据10的程序制备得到4mg产物,收率为10%。m/z预测值:445.48,实测值:445.99;1H NMR(500MHz DMSO)δ11.05(s,1H),10.25(d,J=14.9Hz,1H),8.72(s,1H),8.25(d,J=9Hz,1H),8.14-8.13(m,1H),8.12(s,1H),8.11-8.10(m,1H),8.07(dd,J=8.9Hz,2.6Hz,1H),7.74(s,1H),7.06(s,1H),6.93-6.81(m,1H),6.11(dd,J=16.5Hz,2.5Hz,1H),5.70-5.66(m,1H),4.05-4.00(m,2H),3.30-3.26(m,1H),3.11-3.06(m,1H),2.85-2.75(m,1H),1.99(s,1H),1.75-1.74(m,2H),1.39-1.38(m,1H)。
(R)-3-((6-(6-溴吡啶酰胺)吡啶-3-基)氨甲酰基)哌啶-1-羧酸叔丁酯(25)
根据22的相同程序制备得到505mg产物,收率为59%。m/z ESI预计值:504.39,实测值(M+H)+:505.76。1H NMR(500MHz DMSO-d6):δ10.24(s,1H),10.10(s,1H),8.61(s,1H),8.20-8.18(m,2H),8.08(dd,J=8.9Hz,2.6Hz,1H),8.04(t,J=7.8Hz,1H),7.96(d,J=7.85Hz,1H),4.03(s,1H),3.87-3.84(m,1H),2.81-2.76(m,2H),2.47-2.43(m,1H),1.97-1.93(m,1H),1.73-1.70(m,1H),1.67-1.61(m,1H),1.40(s,9H),1.38-1.36(m,2H)。
(R)-N-(5-(1-丙烯酰基哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(26)
根据13的程序制备得到83mg产物,无需进一步纯化即可继续使用。m/z ESI预测值:458.32,实测值(M+H)+:459.75
(R)-N-(5-(1-丙烯酰基哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(028)
根据10的程序制备得到8mg产物,收率为21%。m/z预测值:445.19,实测值:445.99;1H NMR(500MHz DMSO)δ11.04(s,1H),10.25(d,J=15.0Hz,1H),8.71(s,1H),8.26(d,J=10Hz,1H),8.14-8.13(m,1H),8.12(s,1H),8.11-8.10(m,1H),8.07(dd,J=9.0Hz,2.7Hz,1H),7.73(s,1H),7.06(s,1H),6.93-6.83(m,1H),6.11(dd,J=16.5Hz,2.5Hz,1H),5.69-5.66(m,1H),4.53–4.51(m,1H),4.29–4.26(m,1H),3.30-3.26(m,1H),3.11-3.06(m,1H),2.85-2.75(m,1H),1.99(s,1H),1.75-1.74(m,2H),1.39-1.38(m,1H)。
向(S)-N-(5-(1-丙烯酰基哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(30mg,0.065mmol)的1,4-二烷(2mL)溶液中添加4-(4,4,5,5-四甲基-1,3,2-二硼烷-2-基)异唑(16.6mg,0.085mmol),随后添加2M Na2CO3(aq)(0.163mL,0.325mmol)。将混合物在超声仪中脱气2分钟。添加Pd(dppf)Cl2(5.71mg,0.0078mmol)和t-BuXPhos(4.96mg,0.0117mmol),并将混合物在密封瓶中加热至90℃,持续1小时。用水(5mL)淬灭反应,并用乙酸乙酯(2x10mL)萃取,用盐水洗涤,MgSO4干燥和真空浓度。通过反相HPLC纯化粗品,以获得所需化合物(7mg,收率26%)。m/z预测值:446.47,实测值:446.97;1H NMR(500MHz DMSO)δ10.7(s,1H),10.26(d,J=14.95Hz,1H),9.9(s,1H),9.54(s,1H),8.68(s,1H),8.22(d,J=8.9Hz,1H),8.18-8.15(m,1H),8.12(s,1H),8.11-8.10(m,1H),8.09-8.08(m,1H),6.93-6.81(m,1H),6.11(dd,J=16.5Hz,2.5Hz,1H),5.70-5.66(m,1H),4.53-4.51(m,1H),4.3-4.28(m,1H),4.16-4.13(m,1H),4.05-4.02(m,1H),3.11-3.06(m,1H),2.89-2.73(m,1H),2.02–2.00(m,1H),1.77-1.75(m,2H),1.39-1.38(m,1H)。
根据029的程序制备得到14mg产物,收率为51%。m/z预测值:446.47,实测值:447.25;1H NMR(500MHz DMSO)δ10.7(s,1H),10.26(d,1H,J=14.95Hz),9.9(s,1H),9.54(s,1H),8.68(s,1H),8.22(d,1H,J=8.9Hz),8.18-8.15(m,1H),8.12(s,1H),8.11-8.10(m,1H),8.09-8.08(m,1H),6.93-6.81(m,1H),6.11(dd,1H,J=16.5Hz,2.45Hz),5.70-5.66(m,1H),4.54–4.52(m,1H),3.3-3.25(m,1H),3.11-3.06(m,1H),2.85-2.74(m,1H),2.02–2.00(m,1H),1.77-1.75(m,2H),1.40-1.38(m,1H)。
实施例5:化合物031-034的制备
路线5:
6-溴-N-(3-氟-4-硝基苯基)吡啶酰胺(31)
根据3的程序制备得到3.1g产物,无需进一步纯化即可用于下一步。m/z ESI预测值:340.11,实测值(M+H)+:341.28
N-(4-氨基-3-氟苯基)-6-溴化吡啶酰胺(32)
根据4的程序制备得到所需产物,无需进一步纯化即可用于下一步。m/z ESI预测值:310.13
(S)-3-((4-(6-溴吡啶酰胺)-2-氟苯基)氨甲酰基)哌啶-1-羧酸叔丁酯(33)
根据22的程序制备得到445mg产物,收率为53%。m/z ESI预测值:521.39,实测值(M+H)+:522.8。1H NMR(500MHz DMSO-d6):δ10.57(s,1H),9.74(s,1H),8.13(dd,J=7.6Hz,1.1Hz,1H),8.0(t,J=10Hz,1H),7.93(dd,J=7.9Hz,1.1Hz,1H),7.89(dd,J=13.1Hz,2.4Hz,1H),7.81–7.74(m,1H),7.65–7.62(m,1H),4.05–4.01(m,1H),3.98-3.85(m,1H),2.79–2.74(m,1H),2.63-2.57(m,1H),1.99-1.93(m,2H),1.71-1.69(m,2H),1.64-1.56(m,1H),1.40(s,9H),1.39-1.38(m,2H)。
(S)-N-(4-(1-丙烯酰基哌啶-3-羧酰氨基)-3-氟苯基)-6-溴化吡啶酰胺(34)
根据13的程序制备得到89mg产物,其无需进一步纯化即可使用。m/z ESI预测值:475.32,实测值(M+H)+:476.32
(S)-N-(4-(1-丙烯酰基哌啶-3-羧酰氨基)-3-氟苯基)-6-(1H-吡唑-5-基)吡啶酰胺(031)
根据10的程序制备得到所需化合物(9mg,收率24%)。m/z预测值:462.49,实测值:463.22;1H NMR(500MHz DMSO)δ10.72(s,1H),9.79(s,1H),8.15-8.10(m,2H),8.08–8.06(m,1H),7.92(dd,1H,J=12.9Hz,2.3Hz),7.87–7.80(m,1H),7.74(s,1H),7.65–7.64(d,1H,J=6.2Hz),7.2(s,1H),6.93–6.81(m,1H),6.1(d,1H,J=16.4Hz),5.69–5.67(m,1H),4.52–4.50(m,1H),4.28–4.25(m,1H),4.12–4.01(m,1H),3.09–3.05(m,1H),2.83-2.75(m,1H),2.64–2.58(m,1H),2.00-1.98(m,1H),1.79-1.70(m,2H),1.71-1.69(m,2H),1.38-1.37(m,1H)。
根据029的程序制备得到所需化合物(7mg,收率26%)。m/z预测值:463.47,实测值:463.88;1H NMR(500MHz DMSO)δ10.91(s,1H),10.59(s,1H),9.78(d,J=24.9Hz,1H),9.01(d,J=7.0Hz,1H),8.24–8.21(m,1H),8.05-8.01(m,1H),7.93-7.88(m,1H),7.83-7.75(m,1H),7.61-7.49(m,2H),6.91–6.8(m,1H),6.53(s,1H),6.1(d,J=16.5Hz,1H),5.69-5.67(m,1H),4.51–4.49(m,1H),4.28–4.24(m,1H),4.1–4.01(m,2H),3.09-3.04(m,1H),2.80-2.77(m,1H),2.64–2.60(m,1H),1.99–1.97(m,1H),1.75-1.68(m,2H),1.37-1.36(m,1H)。
(R)-3-((4-(6-溴吡啶酰胺)-2-氟苯基)氨甲酰基)哌啶-1-羧酸叔丁酯(37)
根据22的程序制备得到444mg产物,收率为53%。m/z ESI预测值:521.39,实测值(M+H)+:522.7。1H NMR(500MHz DMSO-d6):δ10.57(s,1H),9.74(s,1H),8.13(dd,J=7.6Hz,1.1Hz,1H),8.0(t,J=10Hz,1H),7.93(dd,J=7.9Hz,1.1Hz,1H),7.89(dd,J=13.1Hz,2.4Hz,1H),7.81–7.75(m,1H),7.65–7.63(m,1H),4.05–4.01(m,1H),3.87-3.84(m,1H),2.79–2.74(m,1H),2.62-2.57(m,1H),1.96-1.93(m,2H),1.71-1.69(m,2H),1.64-1.56(m,1H),1.40(s,9H),1.39-1.38(m,2H)。
(R)-N-(4-(1-丙烯酰基哌啶-3-羧酰氨基)-3-氟苯基)-6-溴化吡啶酰胺(38)
根据13的程序制备得到88mg产物,其无需进一步纯化即可使用。m/z ESI预测值:475.32,观测值(M+H)+:476.32
(R)-N-(4-(1-丙烯酰基哌啶-3-羧酰氨基)-3-氟苯基)-6-(1H-吡唑-5-基)吡啶酰胺(033)
根据10的程序制备得到14mg产物,收率为35%。m/z预测值:462.49,实测值:463.22;1H NMR(500MHz DMSO)δ10.72(s,1H),9.79(s,1H),8.15-8.10(m,2H),8.08–8.07(m,1H),7.92(dd,1H,J=12.9Hz,2.3Hz),7.87–7.80(m,1H),7.74(s,1H),7.65–7.64(d,1H,J=6.2Hz),7.2(s,1H),6.93–6.81(m,1H),6.1(d,1H,J=16.4Hz),5.69–5.67(m,1H),4.52–4.50(m,1H),4.28–4.25(m,1H),4.12–4.01(m,1H),3.09–3.05(m,1H),2.83-2.75(m,1H),2.66–2.60(m,1H),2.00-1.98(m,1H),1.79-1.70(m,2H),1.71-1.69(m,2H),1.38-1.37(m,1H)。
根据029的程序制备得到8mg产物,收率为27%。m/z预测值:463.47,实测值:463.88;1H NMR(500MHz DMSO)δ10.91(s,1H),10.59(s,1H),9.79(d,J=24.2Hz,1H),9.02(d,J=10.2Hz,1H),8.23–8.20(m,1H),8.03-8.00(m,1H),7.92-7.86(m,1H),7.83-7.75(m,1H),7.62-7.48(m,2H),6.92–6.8(m,1H),6.52(s,1H),6.1(d,J=16.5Hz,1H),5.69-5.66(m,1H),4.51–4.49(m,1H),4.26–4.24(m,1H),4.09–4.01(m,1H),3.09-3.04(m,1H),2.80-2.73(m,1H),2.64–2.59(m,1H),1.99–1.97(m,1H),1.75-1.68(m,2H),1.37-1.36(m,1H)。
实施例6:化合物035和036的制备
路线6:
6-溴-N-(5-乙炔基吡啶-2-基)吡啶酰胺(42)
根据22的程序制备得到550mg产物,收率为24%。m/z ESI预测值:302.15,观测值(M+H)+:304.87。1H NMR(500MHz DMSO-d6):δ10.25(s,1H),8.23(d,J=9.6Hz,1H),8.18(dd,J=7.5Hz,1Hz,1H),8.03(dd,J=10Hz,5Hz,1H),7.99(dd,J=8.6Hz,2.3Hz,1H),7.96(dd,J=7.9Hz,1.0Hz,1H),4.38(s,1H)。
(R)-3-叠氮基哌啶-1-羧酸叔丁酯(44)
在0℃下,向含有(S)-3-羟基哌啶-1-羧酸叔丁酯(1g,4.96mmol)的DCM(5mL)的烧瓶中添加TEA(1.38mL,9.92mmol),并且滴加甲磺酰氯(0.46mL,5.96mmol)并搅拌直至反应完成。真空蒸发溶剂,将粗产物溶解在乙酸乙酯中并用NaHCO3(aq)(3x10mL)洗涤。用盐水洗涤有机层,MgSO4干燥,浓缩。将粗品溶解在DMF(2mL)中,加入NaN3(2.56g,39.68mmol),在100℃下搅拌直至初始甲磺酸酯原料消耗。将反应混合物用乙酸乙酯稀释,用NaHCO3(aq)(3x10mL)洗涤。用盐水洗涤有机层,MgSO4干燥,浓缩。通过快速层析(含2%-25%乙酸乙酯的己烷)纯化粗品,得到479mg产物,收率为43%。m/z预测值:226.28,实测值:170.91(无BOC基团);1H NMR(500MHz DMSO)δ3.69(s,1H),3.58-3.40(m,2H),3.29-3.17(m,2H),1.82(s,1H),1.58(s,2H),1.4(s,9H),1.38-1.35(m,1H)。
(R)-3-(4-(6-(6-溴吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸叔丁酯(45)
向含有在1:1:1DMF:水:叔丁醇(3mL)中的6-溴-N-(5-乙炔基吡啶-2-基)吡啶酰胺(150mg,0.49mmol)中添加(R)-3-叠氮基哌啶-1-羧酸叔丁酯(110.88mg,0.49mmol)、CuSO4.5H2O(125mg,0.49mmol)、抗坏血酸钠(99.1mg,0.49mmol),并且在60℃下搅拌直至反应完全。用水淬灭反应混合物,过滤。将固体溶解在DMSO中,并通过反相HPLC纯化,得到189mg产物,收率73%。m/z预测值:528.41,实测值:528.74
(3R)-3-(4-(6-(6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸叔丁酯(46)
根据10的程序制备得到所需化合物(42mg,收率74%)。m/z预测值:599.7,实测值:600.23;1H NMR(500MHz,DMSO)δ11.17(s,1H),10.65(s,1H),8.94(dd,J=19Hz,2.4Hz,1H),8.79(d,J=5.4Hz,1H),8.42-8.39(m,1H),8.35-8.33(m,1H),8.15-8.13(m,3H),7.74(s,1H),7.17(s,1H),7.07(s,1H),5.54(d,J=12.4Hz,1H),4.62(s,1H),4.21-4.00(m,1H),3.82-3.68(m,2H),3.51-3.26(m,2H),3.04(s,2H),2.27-2.25(m,1H),2.21-2.13(m,1H),2.03-1.99(m,1H),1.83(s,1H),1.77-1.68(m,1H),1.63-1.54(m,2H),1.40(s,9H)。
(R)-N-(5-(1-(1-丙烯酰基哌啶-3-基)-1H-1,2,3-三唑-4-基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(035)
向(3R)-3-(4-(6-(6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸叔丁酯(150mg,0.25mmol)的二氯甲烷(10mL)溶液中添加三氟乙酸(1mL,10%v/v)并在室温下搅拌直至初始原料消耗。真空除去溶剂,将粗品溶解在THF(2mL)、NaHCO3(aq)(2mL)中,随后添加丙烯酰氯(17.2μL,0.211mmol)并将混合物搅拌15分钟。用水淬灭反应,用乙酸乙酯萃取(3x20mL),合并,用盐水洗涤,MgSO4干燥,通过反相HPLC纯化,得到59mg产物,收率51%。m/z ESI预测值:469.51,实测值:470.01;1HNMR(500MHz,DMSO)δ11.18(s,1H),8.94(s,1H),8.82(s,1H),8.41(d,J=8.6Hz,1H),8.35(dd,J=8.7Hz,2.4Hz,1H),8.17-8.13(m,3H),7.74(s,1H),7.07(s,1H),6.89-6.84(m,1H),6.17-6.09(m,1H),5.74-5.67(m,1H),4.68-4.62(m,2H),4.33-4.02(m,2H),3.75-3.71(m,1H),3.29-3.22(m,1H),3.09-3.05(m,1H),2.35-2.30(m,1H),2.21-2.17(m,1H),1.91-1.88(m,1H),1.61(s,1H)。
(S)-3-叠氮基哌啶-1-羧酸叔丁酯(48)
根据44的程序制备得到600mg产物,收率为53%。m/z预测值:226.28,实测值:170.91(无BOC基团);1H NMR(500MHz DMSO)δ);1H NMR(500MHz DMSO)δ3.69(s,1H),3.58-3.40(m,2H),3.29-3.17(m,2H),1.82(s,1H),1.58(s,2H),1.4(s,9H),1.38-1.35(m,1H)。
(S)-3-(4-(6-(6-溴吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸叔丁酯(49)
根据45的程序制备得到193mg产物,收率为74%。m/z预测值:528.41,实测值:528.98;1H NMR(500MHz DMSO)δ);1H NMR(500MHz DMSO)δ10.26(s,1H),8.87(s,1H),8.79(s,1H),8.36(s,1H),8.21(d,J=7.5Hz,1H),8.06(t,J=7.6Hz,1H),7.99(d,J=7.9Hz,1H),4.62(s,1H),4.21(s,2H),3.77(s,1H),3.52-3.25(m,1H),3.04(s,1H),2.27-2.24(m,1H),2.17-2.11(m,1H),1.86-1.81(m,1H),1.62-1.55(m,1H),1.39(s,9H)。
(3S)-3-(4-(6-(6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸叔丁酯(50)
根据10的程序制备得到125mg产物,收率为63%。m/z预测值:599.7,实测值:600.23;1H NMR(500MHz,DMSO)δ10.65(s,1H),8.91(dd,J=18.7Hz,3Hz,1H),8.78(d,J=5.1Hz,1H),8.42-8.39(m,1H),8.36-8.33(m,1H),8.23,-8.22(m,1H),8.16-8.13(m,3H),8.07(d,J=2.5Hz,1H),7.74(s,1H),7.18(s,1H),7.08(s,1H),5.54(d,J=12.4Hz,1H),4.62(s,1H),4.00-3.96(m,1H),3.72-3.66(m,1H),3.04(s,1H),2.27-2.21(m,1H),2.17-2.11(m,2H),2.02-1.98(m,1H),1.83(s,1H),1.75-1.68(m,1H),1.59-1.57(m,1H),1.39(s,9H)。
(S)-N-(5-(1-(1-丙烯酰基哌啶-3-基)-1H-1,2,3-三唑-4-基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(036)
根据035的程序制备得到49mg产物,收率为62%。m/z预测值:469.51,实测值:470.01;1H NMR(500MHz,DMSO)δ11.18(s,1H),8.94(s,1H),8.82(s,1H),8.41(d,J=8.5Hz,1H),8.34(dd,J=8.6Hz,2.4Hz,1H),8.17-8.12(m,3H),7.74(s,1H),7.07(s,1H),6.89-6.84(m,1H),6.17-6.09(m,1H),5.74-5.67(m,1H),4.68-4.62(m,2H),4.33-4.13(m,1H),4.05-3.71(m,1H),3.29-3.22(m,1H),3.09-3.05(m,1H),2.36-2.31(m,1H),2.21-2.17(m,1H),1.88(s,1H),1.61(s,1H)。
实施例7:化合物037、024和025的制备
路线7:
3-叠氮基-5-((叔丁氧羰基)氨基)哌啶-1-羧酸苄酯(53)
根据44的程序制备得到410mg产物,收率为38%。m/z预测值:275.31,实测值:275.85(无BOC基团);1H NMR(500MHz DMSO)δ7.37-7.29(m,5H),6.96(d,J=7.9Hz,1H),5.1(s,2H),4.05–3.99(m,1H),3.66-3.60(m,1H),3.41(s,1H),2.64(s,1H),2.16-2.14(m,1H),1.83(s,1H),1.4(s,2H),1.38(s,9H)。
3-(4-(6-(6-溴吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)-5-((叔丁氧羰基)氨基)哌啶-1-羧酸苄酯(54)
根据45的程序制备得到80mg产物,收率为56%。m/z预测值:677.56,实测值:677.03。1H NMR(500MHz DMSO)δ10.26(s,1H),8.87(s,1H),8.79(s,1H),8.34(s,2H),8.22(d,J=6.5Hz,1H),8.06(t,J=7.5Hz,1H),7.99(d,J=9Hz,1H),7.39-7.36(m,4H),7.33-7.32(m,1H),7.20-7.17(m,1H),5.15(s,2H),4.77(s,2H),4.44-4.42(m,1H),4.19-4.17(m,1H),3.61(s,1H),2.44-2.42(m,2H),2.01-1.98(m,1H),1.4(s,9H)。
3-((叔丁氧羰基)氨基)-5-(4-(6-(6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸苄酯(55)
根据10的程序制备得到100mg产物,收率为43%。m/z预测值:748.85,实测值:749.23。1H NMR(500MHz DMSO)δ11.17(s,1H),10.64(s,1H),8.92(dd,J=19.8Hz,2.8Hz,1H),8.90-8.79(m,1H),8.40(dd,J=8.7Hz,6.5Hz,1H),8.36-8.33(m,1H),8.16-8.13(m,2H),7.74(s,1H),7.39-7.31(m,5H),7.20-7.17(m,1H),7.07(s,1H),5.54(dd,J=10Hz,2.4Hz,1H),5.16(s,2H),4.77(s,2H),4.45-4.43(m,1H),4.20-4.17(m,1H),3.99-3.97(m,1H),3.71-3.62(m,2H),3.13(s,1H),2.63(s,1H),2.46-2.43(m,1H),2.22-2.14(m,1H),2.02-1.97(m,2H),1.76-1.73(m,1H),1.61-1.57(m,1H),1.4(s,9H)。
N-(5-(1-(5-丙烯酰胺-1-甲基哌啶-3-基)-1H-1,2,3-三唑-4-基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(037)
向含在乙醇(5mL)中的10%Pd/C(1.42mg,0.0134mmol)的烧瓶中添加3-((叔丁氧羰基)氨基)-5-(4-(6-(6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡啶酰胺)吡啶-3-基)-1H-1,2,3-三唑-1-基)哌啶-1-羧酸苄酯(100mg,0.134mmol),并且在氢气气氛下于50℃搅拌直至反应完成。通过硅藻土垫过滤反应混合物,用乙酸乙酯洗涤并真空去除溶剂。将粗品溶解在1,2二氯乙烷中,向其中加入37%甲醛水溶液(0.0335mL,0.45mmol)和DIEA(0.068mL,0.39mmol)并在室温下搅拌30分钟。添加NaB(OAc)3H(96.4mg,0.45mmol)并搅拌反应直至完全。淬灭反应混合物,用乙酸乙酯萃取,用MgSO4干燥并浓缩。然后将粗品进行进行与47类似的程序并通过反相HPLC纯化以获得15mg产物,收率为24%。m/z预测值:498.55,实测值:499.04。1H NMR(500MHz DMSO)δ11.18(s,1H),8.95(s,1H),8.85(s,1H),8.55(s,1H),8.43(d,J=8.6Hz,1H),8.35(dd,J=8.5Hz,2.4Hz,1H),8.16-8.14(m,3H),7.75(s,1H),7.07(s,1H),6.27-6.15(m,2H),5.71(dd,J=9.8Hz 2.5Hz,1H),5.05(s,1H),4.31(s,1H),3.95(s,1H),3.65-3.56(m,2H),2.57-2.54(m,1H),2.95(s,3H),2.91(s,1H),2.22-2.08(m,1H)
根据029的程序制备得到1mg产物,收率为5%。m/z预测值:482.5,实测值:483.17
N-(5-(1-(2-丙烯酰基-2-氮杂螺[3.3]庚-6-基)-1H-1,2,3-三唑-4-基)吡啶-2-基)-6-(1H-吡唑-4-基)吡啶酰胺(025)
根据10的程序制备得到14mg产物,收率为49%。m/z预测值:481.52,实测值:481.86。
实施例8:化合物013和038的制备
路线8:
N-(5-((3R,5S)-5-丙烯酰胺-1-甲基哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(59)
向搅拌的8(200mg,0.35mmol)在DCM(10mL)的溶液中添加TFA(1mL)。将反应混合物在室温下搅拌30分钟,并除去溶剂。将混合物溶解在DCM(10mL)中。添加DIEA(610μL,3.5mmol),然后添加37%甲醛水溶液(142μL,1.75mmol)。将混合物搅拌10分钟,然后添加三乙酰氧基硼氢化钠(222mg,1.05mmol),并将混合物在室温下搅拌2hr。用饱和NaHCO3水溶液淬灭反应,并用DCM萃取。将合并的有机层用MgSO4干燥,过滤和浓缩以得到59,棕色油状物,其无需进一步纯化即可使用。m/z预测值:487.36,实测值:488.74
N-(5-((3R,5S)-5-丙烯酰胺-1-甲基哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(013)
根据10的相同程序制备得到12mg产物,收率为38%。m/z预测值:474.53,实测值:475.26。1H NMR(500MHz DMSO)δ11.03(s,1H),10.51(s,1H),9.98(s,1H),8.67(s,1H),8.44(d,J=7.9Hz,1H),8.28(d,J=8.8Hz,1H),8.16-8.09(m,3H),8.07(dd,J=8.9Hz,2.9Hz,1H),7.74(s,1H),7.05(s,1H),6.27-6.19(m,1H),6.15(dd,J=17.1Hz,2.6Hz,1H),5.68(dd,J=9.7Hz,2.7Hz,1H),3.03-2.98(m,2H),2.90(s,3H),2.77(s,2H),2.27-2.24(m,2H),1.62-1.55(m,2H)。
N-(5-((3R,5S)-5-丙烯酰胺-1-(2,2,2-三氟乙基)哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(61)
向搅拌的8(200mg,0.35mmol)在DCM(10mL)的溶液中添加TFA(1mL)。将反应混合物在室温下搅拌30分钟,并除去溶剂。将混合物溶解在THF(10mL)中。添加DIEA(610μL,3.5mmol),随后添加2,2,2-三氟甲磺酸三氟乙酯(252μL,1.75mmol)。将混合物在室温下搅拌2hr。用饱和水溶液NaHCO3淬灭反应并用EtOAc萃取。将合并的有机层用MgSO4干燥,过滤和浓缩,得到61,棕色油状物,其无需进一步纯化即可使用。m/z预测值:555.36,实测值:556.43
N-(5-((3R,5S)-5-丙烯酰胺-1-(2,2,2-三氟乙基)哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(038)
根据10的相同程序制备得到32mg产物,收率为46%。m/z预测值:542.52,实测值:543.19。1H NMR(500MHz DMSO)δ11.03(s,1H),10.30(s,1H),8.70(s,1H),8.25(d,J=8.9Hz,2H),8.14-8.10(m,4H),8.07(dd,J=9.0Hz,2.7Hz,1H),7.74(s,1H),7.06(s,1H),6.22-6.17(m,1H),6.10(dd,J=17.2Hz,2.5Hz,1H),5.61(dd,J=10Hz,2.4Hz,1H),3.36-3.27(m,3H),3.12-3.03(m,3H),2.77-2.72(m,1H),2.16-2.12(m,1H),2.04-2.02(m,1H),1.49-1.41(m,1H)。
N-(5-((3R,5S)-5-丙烯酰胺-1-(2,2-二氟乙基)哌啶-3-羧酰氨基)吡啶-2-基)-6-溴化吡啶酰胺(63)
按照61的相同程序,使用三氟甲磺酸2,2-二氟乙酯制备得到棕色油,其无需进一步纯化即可使用。m/z预测值:537.37,实测值:538.61
N-(5-((3R,5S)-5-丙烯酰胺-1-(2,2-二氟乙基)哌啶-3-羧酰氨基)吡啶-2-基)-6-(1H-吡唑-5-基)吡啶酰胺(039)
根据10的相同程序制备得到46mg产物,收率为57%。m/z预测值:524.53,实测值:525.67。1H NMR(500MHz DMSO)δ11.04(s,1H),10.39(s,1H),8.68(s,1H),8.26(d,J=8.8Hz,1H),8.15-8.09(m,4H),8.07(dd,J=9.0Hz,2.7Hz,1H),7.74(s,1H),7.06(s,1H),6.23-6.18(m,1H),6.13(dd,J=17.1Hz,2.6Hz,1H),5.64(dd,J=9.8Hz,2.5Hz,1H),3.27(s,1H),2.89(m,2H),2.71(s,1H),2.14-2.11(m,1H),1.75-1.68(m,1H),1,56-1.49(m,2H),1.44-1.38(m,2H),1.35-1.3(m,1H)。
实施例9:生物学测定
为测量本文化合物对IRAK4的IC50值,使用了Z’-LYTE测定(ThermoFisher)。简言之,将2.5μL在1%DMSO中的不同浓度的化合物添加到在384孔板(康宁目录号#3676)的每个孔中的2.4μL激酶缓冲剂(50mM HEPES pH 7.5,0.01%BRIJ-35,10mM MgCl2,1mM EGTA)中。将5μL 2X IRAK4/Ser/Thr 07混合物(在50mM HEPES pH 7.5,0.01%BRIJ-35,10mM MnCl2,2mM DTT和0.02%NaN3中制备)和2.5μL 4X ATP溶液(4X ATP,50mM HEPES,pH 7.5,0.01%BRIJ-35,10mM MgCl2,1mM EGTA)添加到每个孔中。将板振荡30秒,然后在室温下孵育60分钟。将5μL的1:100000稀释的显色剂A添加到每个孔中。将板振荡30秒,然后在室温下孵育60分钟。随后在荧光酶标仪上读板,并计算发射比以确定反应磷酸化的Ser/Thr 07比值。发射比=香豆素发射(443nm)/荧光素发射(520nm)。
为测量本文化合物对IRAK1的IC50值,使用了Adapta通用激酶测定(ThermoFisher)。简言之,将100nL在100%DMSO中的不同浓度的化合物添加到384孔板(康宁目录号#4512)的每个孔中。将2.4μL 30mM HEPES,2.5μL 4X ATP溶液(在水中)和5μL 2XIRAK1/组蛋白H3(1-20)肽混合物(在50mM HEPES pH 7.5,0.01%BRIJ-35,10mM MgCl2,1mMEGTA中制备)添加到每个孔中。将板震荡30秒并且1000xg离心1分钟。然后将板在室温下孵育60分钟。将5μL检测混合物添加到每个孔中。将板震荡30秒并且1000xg离心1分钟。然后将板在室温下孵育60分钟。随后在荧光酶标仪上读板,并计算发射比以确定ATP与ADP的比值。发射比=AF647发射(665nm)/铕发射(615nm)。
从这些测定获得的数据如下表2中所示。
表2
化合物编号 | IRAK1 IC<sub>50</sub>(nM) | IRAK4 IC<sub>50</sub>(nM) |
001 | 129 | >10,000 |
002 | 257 | >10,000 |
003 | 671 | >10,000 |
005 | 189 | >10,000 |
006 | 14 | 4000 |
007 | 150 | >10,000 |
013 | 18.5 | >10,000 |
016 | 301 | 9,930 |
024 | 612 | 3,330 |
025 | 26.6 | 1,630 |
026 | 68.1 | >10,000 |
027 | 6.37 | 1,870 |
028 | 12.5 | 722 |
029 | 658 | >10,000 |
030 | 399 | 3,330 |
031 | 40.1 | 1,110 |
032 | 1,190 | >10,000 |
033 | 74.2 | 2,510 |
034 | 344 | 2,010 |
038 | 12.1 | >10,000 |
039 | 14.9 | >10,000 |
从前面的描述中,本领域技术人员将清楚除了这里描述的那些之外,本发明的各种修改。此类修改也旨在落入所附权利要求的范围内。在本申请中引用的每个参考文献,包括但不限于所有专利、专利申请和出版物,均通过引用整体并入本文。
Claims (44)
1.一种式I的化合物:
或其药学上可接受的盐;
其中
A选自以下:3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基;
B、C和D各自独立地是CH、CR5或N,条件是当m是0时,B、C和D不都是CH;
R1是任选地被R8取代1次或2次的5-10元杂芳基;
R3和R4在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、OR9、N(R9)2和SR9,其中烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被1个、2个或3个R9取代;
R5在每次出现时独立地选自以下:卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、OR9、N(R9)2和SR9,其中烷基任选地被1个、2个或3个卤素取代;
R6在每次出现时独立地选自以下:氢、C1-C6烷基和氮保护基团,其中烷基任选地被R9取代;
R7选自以下:氢、C1-C6烷基、OH、CN、NO2、卤素、C1-C6烷氧基和C1-C6烷基胺,其中烷基任选地被1个、2个或3个卤素取代;
R8选自以下:C1-C6烷基、OH、CN、NO2、卤素、C1-C6烷氧基和C1-C6烷基胺,其中烷基任选地被卤素、OH和NH2取代1次、2次或3次;
R9在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C(O)C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基;
替代地,两个R9与其连接的原子一起形成3-8元杂环烷基;
R2选自以下:
L3是键、-NH-或C1-C4亚烷基,任选地其中一个或多个碳独立地被–C(O)–、–O–、–S–、–NRL3a–、–NRL3aC(O)–、–C(O)NRL3a–、–SC(O)–、–C(O)S–、–OC(O)–、–C(O)O–、–NRL3aC(S)–、–C(S)NRL3a–、反式–CRL3b=CRL3b–、顺式–CRL3b=CRL3b–、–C≡C–、–S(O)–、–S(O)O–、–OS(O)–、–S(O)NRL3a–、–NRL3aS(O)–、–S(O)2–、–S(O)2O–、–OS(O)2–、–S(O)2NRL3a–或–NRL3aS(O)2–替代;
RL3a是氢、任选地被R9取代的C1-C6烷基或氮保护基团;
RL3b在每次出现时独立地选自以下:氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-12元杂环烷基、6-10元芳基和5-8元杂芳基,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地,两个RL3b基团与其连接的原子一起形成3-8元环烷基或4-7元杂环烷基,两者任选地被1个、2个或3个R9取代;
L4是键或任选地被1个、2个或3个R9取代的C1-C6烷基;
RE1、RE2和RE3的每一个独立地选自以下:氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-12元环烷基、3-12元杂环烷基、6-12元芳基、和5-12元杂芳基、CN、CH2OREE、CH2N(REE)2、CH2SREE、OREE、N(REE)2、SREE,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地,RE1和RE3,或RE2和RE3,或RE1和RE2连接以形成3-8元环烷基或4-7元杂环烷基,两者任选地被1个、2个或3个R9取代;
每个REE独立地选自以下:氢、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-8元环烷基、3-8元杂环烷基、6-10元芳基和5-10元杂芳基,其中烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地被1个、2个或3个R9取代;
或者,替代地,两个REE基团与其连接的原子一起形成4-7元杂环烷基;
RE5是卤素;
RE6是氢、C1-C6烷基或氮保护基团;
每个Y独立地是O、S或NRE7;
RE7是氢、C1-C6烷基或氮保护基团;
m是0或1;
n是0、1、2或3;和
p是0、1、2、3或4。
14.根据权利要求1-13中任一项所述的化合物,其中B是CH、C是CH和D是N。
15.根据权利要求1-13中任一项所述的化合物,其中B是CR5、C是CH和D是CH。
16.根据权利要求1-13中任一项所述的化合物,其中B是N、C是CH和D是N。
17.根据权利要求1-13中任一项所述的化合物,其中B是CR5、C是CH和D是N。
18.根据权利要求1-17中任一项所述的化合物,其中n是0。
19.根据权利要求1-18中任一项所述的化合物,其中p是0或1。
26.一种药物组合物,其包含根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐,和药学上可接受的载体。
27.一种在有需要的受试者中抑制激酶的方法,其包括向所述受试者施用治疗有效量的根据权利要求1-25中任一项所述的化合物或根据权利要求26所述的药物组合物。
28.根据权利要求27所述的方法,其中所述激酶是白介素-1受体相关激酶1(IRAK1)。
29.一种在有需要的受试者中治疗增殖性疾病的方法,其包括向所述受试者施用治疗有效量的根据权利要求1-25中任一项所述的化合物或根据权利要求26所述的药物组合物。
30.根据权利要求29所述的方法,其中所述增殖性疾病与白介素-1受体相关激酶(IRAK)的过表达相关。
31.根据权利要求29或权利要求30所述的方法,其中所述增殖性疾病与白介素-1受体相关激酶1(IRAK1)的过表达相关。
32.根据权利要求29或权利要求30所述的方法,其中所述增殖性疾病与白介素-1受体相关激酶4(IRAK4)的过表达相关。
33.根据权利要求29所述的方法,其中所述增殖性疾病与白介素-1受体相关激酶(IRAK)的活性异常相关。
34.根据权利要求29所述的方法,其中所述增殖性疾病与白介素-1受体相关激酶(IRAK)的活性增加相关。
35.根据权利要求29-34中任一项所述的方法,其中所述增殖性疾病是癌症。
36.根据权利要求29-34中任一项所述的方法,其中所述增殖性疾病是炎性疾病。
37.根据权利要求29-34中任一项所述的方法,其中所述增殖性疾病是自身免疫性疾病。
38.一种在有需要的受试者中治疗癌症的方法,其包括向所述受试者施用治疗有效量的根据权利要求1-25中任一项所述的化合物或根据权利要求26所述的药物组合物。
40.根据权利要求38或权利要求39所述的方法,其中所述癌症是三阴性乳腺癌(TNBC)。
41.根据权利要求38或权利要求39所述的方法,其中所述癌症是急性髓性白血病(AML)。
42.根据权利要求26-41中任一项所述的方法,其中所述方法还包括施用第二药剂。
43.根据权利要求42所述的方法,其中所述第二药剂是激酶抑制剂。
44.根据权利要求42或权利要求43所述的方法,其中所述第二药剂是布鲁顿氏酪氨酸激酶(BTK)抑制剂。
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